Drug delivery methods and systems

ABSTRACT

A two-part bioactive agent delivery system includes a disposable part, a reusable part, and a solvent removal element. The disposable part includes an agent reservoir, a transdermal patch communicating with the agent reservoir and adapted to transdermally deliver the bioactive agent to a user. The transdermal patch has a bottom surface adapted to contact skin of the user, a top surface opposite the bottom surface, and a gas permeable membrane disposed over the top surface of the transdermal patch. The reusable part includes a power source and control electronics that are adapted to deliver bioactive agent dissolved in a solvent from the agent reservoir to the transdermal patch. The solvent removal element includes a gap disposed between the disposable part and the reusable part to create a flow path for gaseous solvent to flow from the gas permeable membrane to ambient air around the bioactive agent delivery system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/677,494, filed on May 29, 2018, the entirety of which isincorporated by reference herein.

This application may also be related to U.S. patent application Ser. No.15/699,382, filed on Sep. 8, 2017, the entirety of which is incorporatedby reference herein.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

This invention was made with Government support under Contract No.2R22CA171786-04 awarded by the National Institute of Health. TheGovernment has certain rights in the invention.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety to the sameextent as if each individual publication or patent application wasspecifically and individually indicated to be incorporated by reference.

BACKGROUND

Medicinal drugs are given to people to manage or improve their healthfor a variety of reasons, such as to prevent or treat a medicalcondition or disease such as diabetes, Parkinson's disease, ulcerativecolitis, or to manage nicotine or another addiction or dependency, or tomanage pain.

Some medicinal drugs are rapidly metabolized by the body. As a result,multiple doses of the drug over a period of time are often needed toprovide a desired effect. In addition to having desired preventative ortherapeutic effects, medicinal drugs can also have negative side-effectson the body that can range from irritating to life-threatening. Further,a person's body can develop tolerance to a drug, experience a diminishedresponse to the drug after taking it for a period of time, and requirehigher doses to have an effect, resulting in increased drug use andadditional side-effects. It is therefore beneficial to a person taking adrug to minimize the amount of drug he or she takes to prevent orminimize tolerance and other unwanted side-effects while still receivingthe desired therapeutic effect from the drug.

Tobacco use (such as smoking) causes serious health problems and canlead to premature death. According to the United States Center forDisease Control (CDC), tobacco use causes more than 5 million deaths peryear and contributes to the development of serious illnesses such ascancer, diabetes, heart disease, lung disease (bronchitis, chronicairway destruction, emphysema), and stroke. Despite anti-smokingadvertising campaigns, legislation, taxation, and development of smokingcessation products to stop or prevent people from using tobacco, tobaccosales remains a multibillion dollar industry, generating an estimated$35 billion dollars per year in profits. Tobacco initially causesphysical and mood-altering effects that are temporarily pleasing.Further, it is difficult for a person to stop using a tobacco productbecause tobacco contains nicotine. Nicotine is highly addictive, and nothaving the nicotine causes harsh withdrawal symptoms. It is verydifficult for a person to overcome a nicotine addiction and stopsmoking.

Medicinal drugs can be taken by tobacco users to help them overcometheir nicotine addiction. Some products to help a person stop smokingcontain small amounts of nicotine as a medicinal drug to minimizewithdrawal symptoms and gradually wean a person from their nicotineaddiction. Medicinal smoking cessation drugs such as nicotine have to betaken over an extended period of time (often over the course of manymonths) to give the body time to adjust to having less nicotine.Medicinal drugs, medical devices, and other products, including smokingcessation products, are regulated in the United States by the U.S. Foodand Drug Administration (FDA). FDA approved products on the market tohelp a person quit smoking include various medicinal drugs that requirea doctor's prescription as well as over-the-counter products. Theseproducts include capsules or tablets, gums, inhalers, lozenges, nasalsprays, and skin patches. These products have thus far been inadequateto get people to stop smoking: 68.9% of adult cigarette smokers say theywant to stop smoking, and every year some 42.7% make an attempt to stopsmoking, but are unsuccessful.

Existing smoking cessation products and other therapeutic andprophylactic treatments for health issues suffer from a variety ofproblems. They may be inconvenient or socially awkward to use. They mayrequire careful and troublesome tracking of when they were used and howmuch was used to prevent overdosing. They may act too slowly after beingadministered and not produce a desired effect when it's needed. They maynot be readily available when needed (such as while a person issleeping). None have been wholly effective to for preventing or treatingvarious medical or other conditions, and smoking remains a significanthealth and social problem.

Thus, new and improved drug delivery systems for bioactive agents, suchas smoking cessation agents, are needed.

SUMMARY OF THE DISCLOSURE

In general, in one embodiment, a two-part bioactive agent deliverysystem includes a disposable part, a reusable part, and a solventremoval element. The disposable part includes an agent reservoir, atransdermal patch communicating with the agent reservoir and adapted totransdermally deliver the bioactive agent to a user. The transdermalpatch has a bottom surface adapted to contact skin of the user, a topsurface opposite the bottom surface, and a gas permeable membranedisposed over the top surface of the transdermal patch. The reusablepart includes a power source and control electronics that are adapted todeliver bioactive agent dissolved in a solvent from the agent reservoirto the transdermal patch. The solvent removal element includes a gapdisposed between the disposable part and the reusable part to create aflow path for gaseous solvent to flow from the gas permeable membrane toambient air around the bioactive agent delivery system.

This and any other embodiments can include one or more of the followingelements. The gap can extend between parallel features on the disposablepart and the reusable part. The gap can be formed when the disposablepart and the reusable part are releasably engaged. The gap can bemaintained with a spacer disposed between the disposable part and thereusable part. The spacer can extend from the disposable part. Thespacer can extend from the reusable part. The system can further includeat least one drainage port formed in an exterior surface of the reusablepart or the disposable part. The disposable part can further include anagent outlet communicating with the agent reservoir and the transdermalpatch. The agent outlet can be configured to provide the bioactive agentdissolved in the solvent to a space between the transdermal patch andthe vapor permeable membrane. The agent reservoir can include a pistonmovably disposed in a chamber. The system can further include a springextending between the agent reservoir piston and a surface to pressurizethe agent reservoir when the spring is compressed and the agentreservoir contains a quantity of bioactive agent solution. The systemcan further include a bolus chamber communicating with the agentreservoir and an agent outlet, and the bolus chamber can include apiston movably disposed in a chamber. The volume of the bolus chambercan be less than the volume of the agent reservoir. The system canfurther include a valve having a first position communicating the agentreservoir with the bolus chamber and a second position communicating thebolus chamber with the agent outlet. The reusable part can include avalve driver, and the control electronics can be adapted to control thevalve driver to actuate the valve to deliver bioactive agent solutionfrom the agent reservoir to the bolus chamber and from the bolus chamberto the agent outlet. The system can further include a spring extendingbetween the bolus chamber piston and a surface to pressurize the boluschamber when the spring is compressed and the bolus chamber contains aquantity of bioactive agent solution. The system can further include alatch adapted to removably attach the disposable part to the reusablepart. The latch can be positioned on one side of the system and a railcan be positioned along a second side of the system. The disposable partand the reusable part can be configured to slide relative to one anotheralong the rail until the latch is activated to attach the disposablepart to the reusable part. The system can further include a connectiondetector adapted to detect a connection between the disposable part andthe reusable part. The connection detector can include a magnet. Themagnet can be disposed in the disposable part. The magnet can bedisposed in the reusable part. The connection detector further caninclude a magnetoresistive switch.

In general, in one embodiment, a method of delivering bioactive agentincludes: connecting a reusable part of a delivery system to adisposable part of the delivery system to form a flow path between thereusable part and the disposable part, delivering the bioactive agentdissolved in a solvent from a reservoir of the disposable part to atransdermal membrane of the disposable part, and allowing the solvent toevaporate and flow from the transdermal membrane through a gas permeablemembrane and along the flow path to ambient air around the deliverysystem.

This and any other embodiments can include one or more of the followingelements. The method can further include applying the transdermalmembrane to skin of a user. The method can further include deliveringthe bioactive agent to the skin. The delivering step can includecontrolling with the reusable part movement of the bioactive agentdissolved in the solvent from the reservoir to the transdermal membrane.The controlling step can include actuating a valve. The method canfurther include detecting a connection between the disposable part andthe reusable part. The detecting step can include sensing a magneticfield.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 is a perspective view of a two-part bioactive agent deliverysystem according to an embodiment.

FIG. 2 is a perspective view of a partially connected two-part bioactiveagent delivery system according to an embodiment.

FIG. 3 is a perspective view of a portion of the disposable part of thetwo-part bioactive agent delivery system of FIG. 1 or FIG. 2 .

FIG. 4 is an exploded view of the disposable part of the two-partbioactive agent delivery system of FIG. 1 or FIG. 2 .

FIG. 5 is a side view of a chassis of the disposable part of thetwo-part bioactive agent delivery system of FIG. 1 or FIG. 2 .

FIG. 6 is a side view of the two-part bioactive agent delivery system ofFIG. 1 or FIG. 2 .

FIG. 7 is an exploded view of the reusable part of the two-partbioactive agent delivery system of FIG. 1 or FIG. 2 .

FIG. 8 shows a connection sensor for a two-part bioactive agent deliverysystem according to an embodiment.

FIG. 9 is a perspective view of a partially connected two-part bioactiveagent delivery system according to an embodiment.

FIG. 10 is a perspective view of the two-part bioactive agent deliverysystem of FIG. 9 .

FIG. 11 is a top view of the disposable part of the two-part bioactiveagent delivery system of FIG. 9 .

FIG. 12 is a top view of the reusable part of the two-part bioactiveagent delivery system of FIG. 9 .

FIG. 13 is a top view of the two-part bioactive agent delivery system ofFIG. 9 .

FIGS. 14-16 are additional perspective views of the partially connectedtwo-part bioactive agent delivery system of FIG. 9 .

FIG. 17 is another perspective view of the two-part bioactive agentdelivery system of FIG. 9 .

FIG. 18 is a top view of the chassis of the two-part bioactive agentdelivery system of FIG. 9 .

FIGS. 19A-19C are side view of the two-part bioactive agent deliverysystem of FIG. 9 .

FIGS. 20A-20C are perspective views of the disposable part of thetwo-part bioactive agent delivery system of FIG. 9 .

FIG. 21A is another perspective view of the disposable part of thetwo-part bioactive delivery system of FIG. 9 .

FIG. 21B is an exploded view of the disposable part of FIG. 21A.

FIG. 21C is an exploded view of the fluidics assembly of FIGS. 21A and21B.

FIG. 22 is an exploded view of the reusable part of the two-partbioactive agent delivery system of FIG. 9 .

DETAILED DESCRIPTION

Described herein are systems and methods for delivering bioactiveagents. The systems can include two parts: a disposable part and areusable part. The disposable part may include bioactive agent andsystem parts that come into contact with bioactive agent, and thereusable part may not contain bioactive agent and system parts that comeinto contact with bioactive agent.

In some embodiments, the disposable part can include an agent reservoir,a bolus chamber, a valve alternately communicating the reservoir withthe bolus chamber and the bolus chamber with an outlet, a solventremoval element, and a transdermal membrane receiving the agent from theoutlet. The reusable part can include a valve driver and controlelectronics.

These bioactive agent delivery systems described herein can deliver asolution of the bioactive agent to a transdermal patch. Solvent from thebioactive agent solution can evaporate from the transdermal patchthrough the solvent removal element (e.g., a gap between the reusablepart and the disposable part) to control the manner in which thebioactive agent passes from the patch into the user's skin.

A bioactive agent delivery system as described herein may be useful fordelivering a bioactive agent to any part on or in a user's body. In someparticular variations, a bioactive agent delivery system as describedherein may be especially useful for delivering a bioactive agenttopically or transdermally to or through a user's skin to a skin layeror bloodstream. Effective topical or transdermally delivery may be aidedby use of a skin delivery membrane such as described herein fortransferring active agent across the skin that is fully or sufficientlywetted to effectively transfer a dose of bioactive agent to a user'sskin. In some variations, a bioactive agent delivery system may beelectronically controlled, programmable, portable, and/or wearable.

The bioactive agent delivery systems described herein may reproduciblydeliver a fixed amount of a bioactive agent to a user, such as to auser's skin, to have a therapeutic or prophylactic effect on the user.In some variations, the bioactive agent delivery systems may beconfigured to be wearable and to deliver a fixed amount of a bioactiveagent to a user's skin in a relatively thin, quiet, easy to use,convenient, electronically controlled system. The bioactive agentdelivery systems may be configured to be attached to a user's body (suchas for a day or shorter or longer), connect with a user's skin, anddeliver a bioactive agent across the user's skin.

The bioactive agent delivery systems as described herein may be usefulfor delivering a bioactive agent to a user for addiction or dependencymanagement or prevention such as for a drug addiction, for diabetes orother disease management or prevention, for pain management orprevention, or for another therapeutic or prophylactic purpose. Thesystems, devices, and methods may be especially useful for deliveringmultiple doses of a drug or other bioactive agent to a user over timewith a safe, inexpensive, convenient, and easy-to-use system thatminimizes risk of a drug or other bioactive agent overdose.

A bioactive agent delivery system as described herein may be configuredto deliver multiple doses or boluses during the course of a day and/orfor multiple days. Delivering multiple boluses may be especially usefulto help a user control cravings or other withdrawal symptoms bydelivering a bioactive agent dose (e.g., a dose of nicotine) especiallyduring (or before) a time of day when cravings or withdrawal symptomsare normally most troublesome (such as delivering a dose during thenight to prevent cravings upon waking).

Further, having a bioactive agent delivery system with a disposable partmay allow the system to be relatively small or flat and easy to wear.For example, a system may be relatively small or flat because thedisposable part needs only contain a limited amount of bioactive agentand/or the reusable part needs only be imparted with sufficient force orpower for a limited number of dose deliveries before being recharged. Insome examples, a bioactive delivery system as described herein may beless than about 20 mm, less than about 16 mm, less than about 15 mm,less than about 14 mm, less than about 13 mm, less than about 12 mm,less than about 11 mm or less than about 10 mm in thickness and may beless than 40 mm, less than 35 mm in length or width, or less than 30 mmin length or width. In some examples, a system may have less than 1500mm² or less than 1000 mm² top (or bottom) surface area. “Bottom” in thiscontext generally refers the part(s) of the system closest to a user. Ifa system includes a transdermal patch, bottom may refer to thetransdermal patch and to the skin delivery member of a transdermalpatch. A surface area of one side of a skin delivery member may be atleast 100 mm2, at least 500 mm2, at least 1500 mm2, at least 2000 mm2,at least 2500 mm2 at least 3000 mm2 or less than or between any of thesenumbers (such as at least 500 mm2 and less than 2000 mm2).

FIGS. 1 and 2 show a two-part bioactive agent delivery system accordingto an embodiment of this invention. The system 10 has a reusable part 12connectable to a disposable part 14. An adhesive element 16 (such as,e.g., adhesive foam) extends around the periphery of the disposable part14, and a removable release liner 18 covers the adhesive surface of theadhesive element 16. The disposable part 14 also has a reservoir 20containing a solution of the bioactive agent (e.g., nicotine) to bedelivered transdermally to user. The reusable part 12 has controlelectronics, a user interface button 72, and an LED mode statusindicator 24. One or more latches 22 may be used to connect anddisconnect the disposable part 14 from the reusable part 12. An outersurface of the bioactive agent delivery system 10 when the reusable part12 and the disposable part 14 are connected together may have any shape,such as circular, ovoid, rectangular, square, and may be contoured (orable to be contoured) to better fit a user's skin

Further details of the disposable part 14 are shown in FIGS. 3-5 .Mounted on a chassis 26 are the reservoir 20, a bolus chamber 28, and avalve chamber 30. A manifold communicates the reservoir 20 with thevalve chamber 30 and the valve chamber 30 with the bolus chamber 28.Movable pistons 32 and 34 are disposed in the reservoir 20 and boluschamber 28, respectively. A rotatable valve element 36 is disposed invalve chamber 30.

Attached to the underside of chassis 26 (e.g., by heat bonding) are agas permeable membrane 38 (formed, e.g., from Poreflon®polytetrafluoroethylene) and a transdermal drug delivery patch 40 (e.g.,a Celgard® membrane). An upper housing 42 supports latch(es) 22 andpartially covers reservoir 20, valve chamber 30, bolus chamber 28, andchassis 26. An opening 44 in housing 42 leads to a fill port 46 that canbe used to add a solution of the bioactive agent to reservoir 20 andbolus chamber 28. A fill port plug 48 seals fill port 46 after fillingthe reservoir and bolus chamber with a solution of the bioactive agent.

Chassis 26 has supports 53, 54, and 59 engaging the reservoir 20, valvechamber 30, and bolus chamber 28, respectively, to hold the reservoir20, valve chamber 30, and bolus chamber 28 in place. One or more raisedspacers 60 extend upwardly from the top side of chassis 26. Open vents62 in chassis 26 are disposed over the gas permeable membrane 38.Spacers 60 engage the underside of the reusable part 12 to establish agap 64 forming a flow path for evaporated solvent passing fromtransdermal patch 40 through gas permeable membrane 38 and chassis vents62, as described below. In an alternative embodiment, the one or morespacers 60 may extend from the reusable part instead of, or in additionto, the spacer(s) extending from the disposable part. Ramped ledges 99can transition the chassis from a thinner section 56 to a thickersection 58.

FIG. 7 shows components of the reusable part 12. A latch element 86adapted to engage with the latch 22 of the disposable part is formed inan upper housing 70. Disposed between an upper housing 70 and a lowerhousing 74 are a spring assembly 76 for the reservoir 20 and a springassembly 78 for the bolus chamber 28. When the disposable part 14 isengaged and latched with the reusable part 12, the spring assemblies 76and 78 engage with the pistons 32 and 34, respectively, and the springsof the spring assemblies 76, 78 compress to pressurize the bioactiveagent solution in reservoir 20 and bolus chamber 28, respectively. Amotor assembly 80 engages valve element 36 and operates under thecontrol of a microprocessor on the printed circuit board 82 using powerfrom battery 84 to turn valve element 36 between a position in whichreservoir 20 communicates with bolus chamber 28 and a position in whichbolus chamber 28 communicates with patch 40. A control button 72 in theupper housing 70 communicates with the microprocessor. The controlbutton 72 can further serve as a user input mechanism. It may bedepressed, e.g., to power on the electronics; to pair the device with asmartphone application; to provide information about the user, such asthe experience of a craving for a cigarette; or to request a devicestatus update or other information. Status indicator 24 can indicate thestatus of the system, e.g., whether the system is delivering fluid, instand-by mode, or empty of bioactive agent.

The system 10 may be used to deliver a bioactive agent transdermally toa user. Disposable part 14 may be prefilled with a solution of thebioactive agent. The disposable part 14 may be connected to the reusablepart 12 and latched with latch components 22 and 86. This connectioncompresses spring assemblies 76 and 78 against pistons 32 and 34 ofreservoir 20 and bolus chamber 28, respectively, to pressurize thebioactive agent solution in the reservoir 20 and bolus chamber 28.Release liner 18 may be removed so that the adhesive on the underside ofadhesive element 16 can be attached to the user's skin. In response to asignal from the device's microprocessor, motor assembly 80 turnsrotatable valve element 36 to a position in which the contents of boluschamber 28 are delivered through an agent outlet in chassis 26 to aspace between gas permeable membrane 38 and transdermal patch 40. As thebioactive agent moves from the patch 40 into the user's skin, solventfrom the bioactive agent solution evaporates and passes through gaspermeable membrane 38 and the vents 62 in chassis 26 to reach the flowpath defined by gap 64. Removal of solvent from the transdermal patch 40enables the percentage of bioactive agent in liquid solution in thepatch to remain high enough to maintain a desired transdermal deliveryrate of the bioactive agent until essentially all of the bioactive agentin the bolus of bioactive agent solution has been delivered. Subsequentboluses of bioactive agent may be delivered by actuating the valveelement 36 to enable refilling of the bolus chamber 28 with solutionfrom the reservoir 20 followed by movement of the valve element 36 topermit delivery of the next bolus from bolus chamber 28 to thetransdermal patch 40. The timing of the bolus deliveries are under thecontrol of the programmed microprocessor.

Further details of the operation of the reusable and disposable partsand components, including reservoir 20, bolus chamber 28, and valve 36and/or the control button 72 and indicator 24, to deliver the bioactiveagent solution to the transdermal patch at controlled times may be foundin US Publication No. 2016/0220798, the entirety of which isincorporated by reference.

In some embodiments, the systems described herein can include a sensorto detect connection of a disposable part with the reusable part. In oneembodiment shown in FIG. 8 , a system 210 includes a magnetoresistiveswitch 290 disposed in the reusable part 212 that detects a magnet 292disposed in the spring assembly 278. In an alternative embodiment, themagnet can be disposed in the disposable part 214 (see, for example,magnet 392 in FIG. 21B). Use of the magnetoresistive switch 290 enablesthe electronics to be encapsulated and waterproof. In some embodiments,a reed switch or a Hall sensor may be used as an alternative to themagnetoresistive switch. Information about the connection times anddurations of the reusable part with the disposable part may be used,e.g., to monitor compliance with a drug delivery regimen.

Another exemplary two-part bioactive agent delivery system 310 that issimilar to system 10 is shown in FIGS. 9-22 . Referring to FIGS. 9-10 ,system 310 includes a reusable part 312 connectable to a disposable part314, an adhesive element 316, and release liner 318. The reusable part312 has control electronics, a user interface button 372, and an LEDmode status indicator 324. When the reusable part 312 and the disposablepart 314 are connected together, the upper housing 342 of the disposablepart 314 and the housing 370 of the reusable part abut one another tocreate a substantially smooth outer contour.

As shown in FIGS. 11-16 , the system 310 further includes a single latch322 and rail 333 to connect and disconnect the disposable part 314 fromthe reusable part 312. The latch 322 can be on a first side of thedisposable part 314 while the rail 333 can be positioned on a secondopposite side of the disposable part 314. The rail 333 can extendsubstantially parallel with the longitudinal axis of the system 310.Further, the rail 333 can be configured to mate with a sliding element335 (e.g., a c-shaped element) on the housing 730 of the reusable part312. In use, the sliding element 335 can slide along the rail 333 as thedisposable part 314 and reusable part 312 are engaged. The rail 333 canthus advantageously ensure that the disposable part 314 and reusablepart 312 remain aligned as they are connected or disconnected. The latch322 can have a cantilevered first end 361 and a sloped or ramped secondend 366 (see FIG. 11 ). The ramped second end 366 can be connected tothe upper housing 342 of the disposable part 314 while the cantileveredfirst end 361 can be configured to mate with a latch element 386 (e.g.,an opening) on the housing 370 of the reusable part 312. The latch 322and latch element 386 can function to hold the disposable part 314 andreusable part 312 together until the latch 322 is depressed by the user.

Referring to FIGS. 17-19C, the system 310 can include open vents 362through the chassis 326 so as to expose the membrane 338 thereunder. Thevents 362 can be positioned in a central portion of the chassis 326 andcan be cut so as to maximize the exposure of the surface of the membrane338. For example, the vents 362 can expose 5-30% of the surface of themembrane 338, such as 10-20% of the surface. Diagonal struts 375 canextend between the vents 362 to maintain the strength of the chassis362. The vents 326 can connect to gap 364 between the reusable part 312and the disposable part 314. The gap 364 can be formed between theparallel bottom surface 381 of the reusable part 312 and top surface 383of the disposable part 314. The gap 364 can be formed by the frameworkof the system, including the mating between the rail 333 and slidingelement 335 and the mating between the latch 322 and latch element 382.Additionally, one or more spacers 360 can be configured to help maintainthe gap 364. The spacers 360 can be, for example, cylindrical orsemi-spherical elements that protrude upwards (i.e., from the topsurface 383 of) the chassis 326. Further, the spacers 360 can bepositioned on a side of the chassis 360 that is opposite to thereservoir 320, bolus chamber 320, and valve chamber 330 (e.g., on thethinner section 356). There can be a plurality of spacers 360, such as3-5 spacers 360, that are substantially equally spaced around the vents362. Each of the spacers 360 can have a small diameter (e.g., a diameterthat is less than 10% of the width of the chassis 26). Additionally,ramped ledges 399 can transition between the thinner section 356 of thechassis 326 and the thicker section 358 of the chassis 326. In someembodiments, there can be two ledges 399 that are axially aligned withone another at approximately the center of the chassis 326.

The spacers 360 can engage the bottom surface 381 of the reusable part312 to maintain the gap 364 and therefore to form a flow path forevaporated solvent passing through the vents 362. In an alternativeembodiment, the one or more spacers may extend from the reusable partinstead of, or in addition to, the spacers extending from the disposablepart. Additionally, the thick section 358 of the chassis 326 can engagethe bottom surface 381 of the reusable part 312 (i.e., can be coincidentwith the bottom of the reusable part 312), which can further maintainthe gap 364 above the thin section 356.

Referring to FIGS. 20A-20C, the system 310 can further include one ormore drainage ports 371 therein that are aligned with or connected withthe gap 364 and can provide drainage for any excess fluid left in theside of the system 310. The drainage ports 371 can be formed in theupper housing 377 of the disposable part 312 proximate to the thickersection 358 of the chassis 326 and can facilitate water drainage (e.g.,from the user bathing and/or otherwise getting fluid in or on the system310). In some embodiments, the drainage ports 371 can be positioned suchthat, when the system is worn on the body (e.g., on the arm) and thedevice 310 is turned vertically, water will exit the device by gravityvia ports 371. The ports 371 can be sized so as to avoid capillarypooling of water therein.

Further details of the disposable part 314 are shown in FIGS. 21A-21C,and further details of the reusable part 312 are shown in FIG. 22 . Thedisposable part 314 can further include a transdermal delivery patch340, a permeable membrane 338 and a foam adhesive 365 with deadeningstrips 364. The deadening strips 364 can provide the user with an edgeor small flap to grab onto to help remove the system 310 from the skin.An opening 344 in housing 342 leads to a fill port 346 that can be usedto add a solution of the bioactive agent to reservoir 320 and boluschamber 328. Movable pistons 332 and 334 are disposed within thereservoir 320 and bolus chamber 328, respectively. The reusable part 312can include a printed circuit board 382 positioned over the lowerhousing 374, bolus spring assembly 378 (to control piston 334),reservoir spring assembly 376 (to control piston 332). A motor 329 cancontrol activation of the valve 336 and spring assemblies 376, 378. Apower supply 384 (e.g., batteries) can provide power to the motor 329. Adetect magnet 392 can be positioned in the disposable part 314 while amagnetoresistive switch 390 can be positioned on the printed circuitboard 382 of the reusable part 312 to detect attachment of thedisposable part 314 to the reusable part 312 (i.e., when the magnet 392and switch 390 are adjacent to one another upon attachment of thereusable part 312 and the disposable part 314).

The system 310 can operate similar to system 10. The disposable part 314may be connected to the reusable part 312 by sliding the rail 333 andsliding element 382 relative to one another until the components arelatched with latch components 322 and 386. This connection compressesspring assemblies 376 and 378 against pistons 332 and 334 of reservoir320 and bolus chamber 328, respectively, to pressurize the bioactiveagent solution in the reservoir 320 and bolus chamber 328. In responseto a signal from the device's microprocessor, motor assembly 380 turnsrotatable valve element 336 to a position in which the contents of boluschamber 328 are delivered to the patient's skin through the transdermaldelivery patch 340. As the bioactive agent moves onto the user's skin,solvent from the bioactive agent solution evaporates through the gaspermeable membrane 338 and the vents 362 in chassis 326 to reach theflow path defined by gap 364. Further details of the operation of thereusable and disposable parts and components to deliver the bioactiveagent solution to the transdermal patch at controlled times may be foundin US Publication No. 2016/0220798, the disclosure of which isincorporated by reference.

It should be understood that any element described herein with respectto one embodiment can be added to or substituted for any elementdescribed with respect to another embodiment.

When a feature or element is herein referred to as being “on” anotherfeature or element, it can be directly on the other feature or elementor intervening features and/or elements may also be present. Incontrast, when a feature or element is referred to as being “directlyon” another feature or element, there are no intervening features orelements present. It will also be understood that, when a feature orelement is referred to as being “connected”, “attached” or “coupled” toanother feature or element, it can be directly connected, attached orcoupled to the other feature or element or intervening features orelements may be present. In contrast, when a feature or element isreferred to as being “directly connected”, “directly attached” or“directly coupled” to another feature or element, there are nointervening features or elements present. Although described or shownwith respect to one embodiment, the features and elements so describedor shown can apply to other embodiments. It will also be appreciated bythose of skill in the art that references to a structure or feature thatis disposed “adjacent” another feature may have portions that overlap orunderlie the adjacent feature.

Terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention.For example, as used herein, the singular forms “a”, “an” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise. It will be further understood that the terms“comprises” and/or “comprising,” when used in this specification,specify the presence of stated features, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, steps, operations, elements, components, and/orgroups thereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items and may beabbreviated as “/”.

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if a device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of over and under. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

Although the terms “first” and “second” may be used herein to describevarious features/elements (including steps), these features/elementsshould not be limited by these terms, unless the context indicatesotherwise. These terms may be used to distinguish one feature/elementfrom another feature/element. Thus, a first feature/element discussedbelow could be termed a second feature/element, and similarly, a secondfeature/element discussed below could be termed a first feature/elementwithout departing from the teachings of the present invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising” means various components can be co-jointlyemployed in the methods and articles (e.g., compositions and apparatusesincluding device and methods). For example, the term “comprising” willbe understood to imply the inclusion of any stated elements or steps butnot the exclusion of any other elements or steps.

As used herein in the specification and claims, including as used in theexamples and unless otherwise expressly specified, all numbers may beread as if prefaced by the word “about” or “approximately,” even if theterm does not expressly appear. The phrase “about” or “approximately”may be used when describing magnitude and/or position to indicate thatthe value and/or position described is within a reasonable expectedrange of values and/or positions. For example, a numeric value may havea value that is +/−0.1% of the stated value (or range of values), +/−1%of the stated value (or range of values), +/−2% of the stated value (orrange of values), +/−5% of the stated value (or range of values), +/−10%of the stated value (or range of values), etc. Any numerical valuesgiven herein should also be understood to include about or approximatelythat value, unless the context indicates otherwise. For example, if thevalue “10” is disclosed, then “about 10” is also disclosed. Anynumerical range recited herein is intended to include all sub-rangessubsumed therein. It is also understood that when a value is disclosedthat “less than or equal to” the value, “greater than or equal to thevalue” and possible ranges between values are also disclosed, asappropriately understood by the skilled artisan. For example, if thevalue “X” is disclosed the “less than or equal to X” as well as “greaterthan or equal to X” (e.g., where X is a numerical value) is alsodisclosed. It is also understood that the throughout the application,data is provided in a number of different formats, and that this data,represents endpoints and starting points, and ranges for any combinationof the data points. For example, if a particular data point “10” and aparticular data point “15” are disclosed, it is understood that greaterthan, greater than or equal to, less than, less than or equal to, andequal to 10 and 15 are considered disclosed as well as between 10 and15. It is also understood that each unit between two particular unitsare also disclosed. For example, if 10 and 15 are disclosed, then 11,12, 13, and 14 are also disclosed.

Although various illustrative embodiments are described above, any of anumber of changes may be made to various embodiments without departingfrom the scope of the invention as described by the claims. For example,the order in which various described method steps are performed mayoften be changed in alternative embodiments, and in other alternativeembodiments one or more method steps may be skipped altogether. Optionalfeatures of various device and system embodiments may be included insome embodiments and not in others. Therefore, the foregoing descriptionis provided primarily for exemplary purposes and should not beinterpreted to limit the scope of the invention as it is set forth inthe claims.

The examples and illustrations included herein show, by way ofillustration and not of limitation, specific embodiments in which thesubject matter may be practiced. As mentioned, other embodiments may beutilized and derived there from, such that structural and logicalsubstitutions and changes may be made without departing from the scopeof this disclosure. Such embodiments of the inventive subject matter maybe referred to herein individually or collectively by the term“invention” merely for convenience and without intending to voluntarilylimit the scope of this application to any single invention or inventiveconcept, if more than one is, in fact, disclosed. Thus, althoughspecific embodiments have been illustrated and described herein, anyarrangement calculated to achieve the same purpose may be substitutedfor the specific embodiments shown. This disclosure is intended to coverany and all adaptations or variations of various embodiments.Combinations of the above embodiments, and other embodiments notspecifically described herein, will be apparent to those of skill in theart upon reviewing the above description.

What is claimed is:
 1. A two-part bioactive agent delivery system, thesystem comprising: a disposable part comprising an agent reservoir, atransdermal patch communicating with the agent reservoir and adapted totransdermally deliver the bioactive agent to a user, the transdermalpatch having a bottom surface adapted to contact skin of the user and atop surface opposite the bottom surface, and a gas permeable membranedisposed over the top surface of the transdermal patch; a reusable partcomprising a power source and control electronics, the controlelectronics being adapted to deliver bioactive agent dissolved in asolvent from the agent reservoir to the transdermal patch; a solventremoval element comprising a gap disposed between the disposable partand the reusable part to create a flow path for gaseous solvent to flowfrom the gas permeable membrane to ambient air around the bioactiveagent delivery system, and wherein the gap is maintained with a spacerdisposed between the disposable part and the reusable part.
 2. Thesystem of claim 1, wherein the gap extends between parallel features onthe disposable part and the reusable part.
 3. The system of claim 1,wherein the gap is formed when the disposable part and the reusable partare releasably engaged.
 4. The system of claim 1, wherein the spacerextends from the disposable part.
 5. The system of claim 1, wherein thespacer extends from the reusable part.
 6. The system of claim 1, furthercomprising at least one drainage port formed in an exterior surface ofthe reusable part or the disposable part.
 7. The system of claim 1,wherein the disposable part further comprises an agent outletcommunicating with the agent reservoir and the transdermal patch.
 8. Thesystem of claim 7, wherein the agent outlet is configured to provide thebioactive agent dissolved in the solvent to a space between thetransdermal patch and the vapor permeable membrane.
 9. The system ofclaim 1, wherein the agent reservoir comprises a piston movably disposedin a chamber.
 10. The system of claim 9, further comprising a springextending between the agent reservoir piston and a surface to pressurizethe agent reservoir when the spring is compressed and the agentreservoir contains a quantity of bioactive agent solution.
 11. Thesystem of claim 9, further comprising a bolus chamber communicating withthe agent reservoir and an agent outlet, the bolus chamber comprising apiston movably disposed in a chamber, the volume of the bolus chamberbeing less than the volume of the agent reservoir.
 12. The system ofclaim 11, further comprising a valve having a first positioncommunicating the agent reservoir with the bolus chamber and a secondposition communicating the bolus chamber with the agent outlet.
 13. Thesystem of claim 12, wherein the reusable part comprises a valve driver,the control electronics being adapted to control the valve driver toactuate the valve to deliver bioactive agent solution from the agentreservoir to the bolus chamber and from the bolus chamber to the agentoutlet.
 14. The system of claim 9, further comprising a spring extendingbetween the bolus chamber piston and a surface to pressurize the boluschamber when the spring is compressed and the bolus chamber contains aquantity of bioactive agent solution.
 15. The system of claim 1, furthercomprising a latch adapted to removably attach the disposable part tothe reusable part.
 16. The system of claim 15, wherein the latch ispositioned on one side of the system and a rail is positioned along asecond side of the system, the disposable part and the reusable partconfigured to slide relative to one another along the rail until thelatch is activated to attach the disposable part to the reusable part.17. The system of claim 1, further comprising a connection detectoradapted to detect a connection between the disposable part and thereusable part.
 18. The system of claim 17, wherein the connectiondetector comprises a magnet.
 19. The system of claim 18, wherein themagnet is disposed in the disposable part.
 20. The system of claim 18,wherein the magnet is disposed in the reusable part.
 21. The system ofclaim 18, wherein the connection detector further comprises amagnetoresistive switch.
 22. A method of delivering a bioactive agent,the method comprising: connecting a reusable part of a delivery systemto a disposable part of the delivery system to form a flow path along agap between the reusable part and the disposable part maintained by aspacer disposed between the disposable part and the reusable part;delivering the bioactive agent dissolved in a solvent from a reservoirof the disposable part to a transdermal membrane of the disposable part;and allowing the solvent to evaporate and flow from the transdermalmembrane through a gas permeable membrane and along the flow path toambient air around the delivery system.
 23. The method of claim 22,further comprising applying the transdermal membrane to skin of a user.24. The method of claim 23, further comprising delivering the bioactiveagent to the skin.
 25. The method of claim 22, wherein the deliveringstep comprises controlling with the reusable part movement of thebioactive agent dissolved in the solvent from the reservoir to thetransdermal membrane.
 26. The method of claim 25, wherein thecontrolling step comprises actuating a valve.
 27. The method of claim22, further comprising detecting a connection between the disposablepart and the reusable part.
 28. The method of claim 27, wherein thedetecting step comprises sensing a magnetic field.